The present invention relates to the synthesis of a beta methyl carbapenem intermediate of the formula: ##STR2##
This intermediate for carbapenem antibiotics has been disclosed in numerous patents and publications. For example, the intermediate is disclosed in U.S. Pat. No. 4,350,631 issued to Christensen, et al. on Sep. 21, 1982 and in U.S. Pat. No. 4,994,568 issued to Christensen on Feb. 19, 1991. In the process described in each of these patents, a diazo compound of the formula: ##STR3## is cyclized using a catalyst or irradiation. These process steps generate a mixture of 1-.alpha. and 1-.beta. methyl isomers, which in turn require separation prior to further chemical modification.
Likewise, a washing step has been utilized in the past, whereby the diazo compound is purified in an aqueous medium. The diazo compound is washed with water, dried and then cyclized. This improves the yield of the 1-.beta. methyl isomer, but introduces water into the reaction, thus necessitating the implementation of the drying step. Drying at this stage in the synthesis of carbapenems can be unpredictable and dangerous.
The present invention overcomes these difficulties, providing an unexpectedly low rate of formation of the 1-.alpha. methyl isomer, and thus eliminating the need for separation of the .alpha. and .beta. isomers prior to further chemical synthesis. Moreover, even in relatively uncontrolled reactions, inclusion of the Lewis acid as described herein in detail can reduce epimerization to the 1-.alpha. methyl compound to less than about one percent.